How antigen exposure shapes the subsequent NK cell response to HIV

抗原暴露如何影响随后的 NK 细胞对 HIV 的反应

基本信息

批准号：
10561720
负责人：
Silke Paust
金额：
$ 41.83万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-18 至 2023-08-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10561720
关键词：
Activities of Daily Living Adaptive Immune System Adoptive Transfer Algorithms Antibodies Antigens Attention B-Lymphocytes Biological Assay CD94 Antigen Cell Differentiation process Cell Surface Receptors Cell surface Cells Cellular biology Collaborations Complex Data Data Analyses Disease Effector Cell Etiology Exposure to Flow Cytometry Glycoproteins Goals HIV HIV Infections HIV envelope protein HIV vaccine Hepatic Herpesvirus Type 3 Human Immunologic Markers Immunologic Memory Immunologist In Vitro Individual Infection Knowledge Learning Life Lymphocyte Measures Mediating Memory Names Natural Killer Cells Nature Outcome Pathway interactions Phenotype Population Pre-Clinical Model Proteins Publishing Risk Sampling Scientist Shapes Signal Transduction T-Lymphocyte Testing Tissues Vaccinated Vaccination Vaccine Design Vaccines Viral Viral Physiology adaptive immunity comparison control efficacy evaluation experience human data human genomics humanized mouse improved in vivo member mouse model neoplastic cell novel novel vaccines peripheral blood pharmacologic receptor response single cell sequencing transcription factor transcriptome vaccine development vaccine efficacy vaccine evaluation viral genomics

项目摘要

The goal of this proposal is to determine how antigen exposure shapes subsequent Natural Killer cell responses to HIV. We propose to identify NK functional subsets in naïve and antigen-primed human NK cells using single-cell sequencing and multi-parametric flow cytometry. We propose to verify the relevance of such functional subsets to NK cell-mediated host protection from HIV disease using our established in vitro and in vivo functional assays. NK cells are innate lymphocytes that live up to their name by their ability to kill infected or tumor cells within minutes of exposure. However, the targeting of NK cell effector functions has not been a significant focus in vaccine development, which has mainly focused on their T and B cell counterparts in the adaptive immune system. Recent findings from the PI of this application indicate that NK cells deserve more attention. We recently published exciting new data that human NK cells remember prior antigen- encounters and mediate enhanced recall responses to HIV-Envelope in humanized mice. Here, we present unpublished new data that HIV-Env-primed memory NK cells suppress HIV viral titers upon experimental viral challenge. These findings have opened the opportunity to harness NK memory functions for vaccine design. However, high NK cell receptor repertoire diversity is associated with an increased risk of HIV acquisition, and NK cell receptor repertoires diversify throughout life, presumably in response to antigen exposure. These data present a challenge for vaccine design, as both protective NK memory responses and potentially risky NK repertoire diversifications are consequences of antigen exposure. The identification of specific functional subsets of HIV-responsive, host-protective NK cells and their mechanisms of host protection is therefore critically needed. Their discovery will open the door for revised vaccine designs that endure the incorporation of NK memory, rather than harmful receptor repertoire diversity, as a host protective outcome. Our data will enable the pre-screening of vaccines for the induction of protective NK functional subsets in pre- clinical models and allow for improved vaccine efficacy evaluations in humans. Thereby, our studies will provide the rationale to develop novel vaccines that exploit the antiviral activity of NK cells to protect humans from HIV infection while avoiding harmful activity.

该提案的目标是确定抗原暴露如何影响随后的自然杀伤细胞我们建议鉴定天然和抗原引发的人类 NK 细胞中的 NK 功能亚群。我们建议使用单细胞测序和多参数流式细胞术来验证相关性。使用我们建立的体外实验，这些功能子集可以帮助 NK 细胞介导的宿主免受 HIV 疾病的保护 NK 细胞是天生的淋巴细胞，其杀伤能力名副其实。然而，NK 细胞效应功能的靶向性却没有。疫苗开发的一个重要焦点，主要集中在 T 细胞和 B 细胞对该应用程序的 PI 的最新发现表明 NK 细胞值得使用。我们最近发表了令人兴奋的新数据，表明人类 NK 细胞会记住先前的抗原 - 在这里，我们提出了在人源化小鼠中遇到并介导对 HIV-Envelope 的增强的回忆反应。未发表的新数据表明 HIV-Env 引发的记忆 NK 细胞在实验病毒时抑制 HIV 病毒滴度这些发现为利用 NK 记忆功能进行疫苗设计提供了机会。然而，高 NK 细胞受体库多样性与感染 HIV 的风险增加相关， NK 细胞受体库在整个生命过程中呈现多样化，大概是对抗原暴露的反应。这些数据对疫苗设计提出了挑战，因为保护性 NK 记忆反应和潜在的有风险的 NK 库多样化是特定抗原暴露的结果。 HIV 反应性、宿主保护性 NK 细胞的功能亚群及其宿主保护机制因此，他们的发现将为改进疫苗设计打开大门，以适应这种情况。 NK 记忆的纳入，而不是有害的受体库多样性，作为宿主的保护结果。我们的数据将能够对疫苗进行预筛选，以在预筛选中诱导保护性 NK 功能子集。临床模型并允许改进人类疫苗功效评估。为开发利用 NK 细胞的抗病毒活性来保护人类的新型疫苗提供依据远离艾滋病毒感染，同时避免有害活动。